Stable formulations for parenteral injection of small molecule drugs

ABSTRACT

Disclosed is a stable liquid formulation for parenteral injection comprising a biocompatible non-aqueous solvent and a small molecule drug, or a salt thereof, solubilized within the non-aqueous solvent, wherein the liquid formulation comprises less than 10% by weight residual water, and wherein the volume of the liquid formulation to be parenterally injected is from 0.1 μl to 3 ml.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/665,021, filed Jun. 27, 2012, the contents of which are incorporatedby reference.

BACKGROUND OF THE INVENTION

A. Field of the Invention

The present invention relates to pharmaceutical formulations and, moreparticularly, to pharmaceutical formulations of small molecule drugshaving improved solubility and stability and to methods of using suchpharmaceutical formulations to treat various diseases, conditions anddisorders.

B. Description of Related Art

While many small molecule drugs are orally bioavailable, parenteralinjection is also used in situations where the drug has insufficientoral bioavailability, the patient is unable to accept drugs orally, orthere is a need for more rapid onset of drug action. For example,administration of benzodiazepines for emergency treatment of epilepticseizures, catecholemines for allergic reactions and “triptans” for thetreatment of migraine headaches represent situations where oraladministration is not as efficient or advisable and thus, the drugs mustbe administered via a non-oral route, often parenteral administration.

Standard practice for preparing formulations containing small moleculedrugs has been to develop aqueous solutions for parenteral injection. Aprimary reason for this is that the majority of the human body is madeup of water, including blood plasma, which is an aqueous environment.Therefore, there is a natural tendency to administer a drug formulationthat is compatible with the environment that the drug is intended toreach. Several small molecule drugs, however, have limited solubilityand poor stability in such aqueous environments. This has been solved,at least in part, by the use of co-solvents and stabilizers to moreefficiently solubilize and stabilize the small molecule drug in aformulation.

An example of some of the difficulties associated with parenteralinjection of small molecule drugs can be seen with diazepam. This drug,which is used for emergency treatment of epileptic seizures, has beenhampered by its poor aqueous solubility. Thus, the currently availableemergency treatment consists of a rectal gel. An attempt has also beenmade to develop a large-volume (up to 3 ml) intramuscular injectionbased on an aqueous formulation with co-solvents (larger volumes areneeded due to lower solubility of diazepam). However, the development ofthis drug has been limited by the difficulty in delivering a deep, largevolume intramuscular injection to a convulsing patient, as well as thepain associated with such a large dosage volume.

Further, due to the stability issues of small molecule drugs in aqueousenvironments, current products are oftentimes sold as lyophilizedpowders that require reconstitution in an aqueous carrier prior toinjection. This allows for longer shelf-life of the drug active. Someproducts are even sold as liquids that require further dilution prior toinjection with sterile water, phosphate buffer solution, or isotonicsaline.

SUMMARY OF THE INVENTION

The present invention provides a solution to the current problems facingthe use of small molecule drugs in therapeutic applications. Inparticular, the solution is premised on solubilizing and stabilizing asmall molecule drug in a non-aqueous environment and then directlyinjecting the solubilized drug into a patient via parenteraladministration. The formulation can be in liquid form. Once theformulation is prepared, it can be stored for an extended period of time(even in an injection device) and directly injected into a subject(e.g., human) without the reconstitution or dilution steps seen incurrent products. Indeed, this solution goes against the prevailingindustry standard. In this regard, the inventors' solution has resultedin a more stable environment for the drug and a more efficient andeffective way to actually provide life-saving drugs to those in need oftreatment. Importantly, the inventors' discovery is widely applicablefor the delivery of numerous small molecule drugs that, like diazepam,have poor or limited stability and solubility in an aqueous environment.

In one aspect of the present invention there is disclosed a stableliquid formulation for parenteral injection comprising a small moleculedrug, or a salt thereof and a biocompatible non-aqueous solvent, whereinthe small molecule drug is solubilized within the non-aqueous solvent.One of the unique aspects of the present invention is that it can beused for a wide variety of small molecule drugs, including those thatcurrently being administered via parenteral injection. Some examplesinclude benzodiazepines, catecholamines, and triptans. In one particularaspect, the compound is a benzodiazepine such as diazepam. Thesolubility of diazepam, by way of example, can be greater than what istypically seen with current products (e.g., the Examples show thatdiazepam solubility in DMSO can approach levels of 500 mM, which wouldallow for a wide range of dosaging options, such as for instance,reduced volumes of dosages—for instance, a diazepam formulation in DMSOcan have 100 mM to 500 mM, 150 mM to 400 mM, 175 mM to 350 mM, or 200 mMto 300 mM of the drug, wherein each concentration provides for asubstantially smaller volume to deliver the same quantity of drugcompared to water-based preparations of diazepam. The Examples also showthat the solubility of diazepam in NMP exceeded 700 mM, which allows foreven smaller dosage volumes as needed). Other non-limiting smallmolecule drugs that can be used in the context of the present inventioninclude epinenpherine, sumatriptan, novantrone, chemotherapy smallmolecules (e.g., mitoxantrone), corticosteroid small molecules (e.g.,methylprednisolone), immunosuppressive small molecules (e.g.,azathioprine, cladribine, cyclophosphamide, methotrexate),anti-inflammatory small molecules (e.g., salicylic acid, acetylsalicylicacid, diflunisal, choline magnesium trisalicylate, salicylate,benorylate, flufenamic acid, mefenamic acid, meclofenamic acid,triflumic acid, diclofenac, fenclofenac, alclofenac, fentiazac,ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen,suprofen, indoprofen, tiaprofenic acid, benoxaprofen, pirprofen,tolmetin, zomepirac, clopinac, indomethacin, sulindac, phenylbutazone,oxyphenbutazone, azapropazone, feprazone, piroxicam, isoxicam), smallmolecules used to treat neurological disorders (e.g., cimetidine,ranitidine, famotidine, nizatidine, tacrine, donepizil, metrifonate,rivastigmine, selegilene, imipramine, fluoxetine, olanzapine,sertindole, risperidone, valproate semisodium, gabapentin,carbamazepine, topiramate, phenyloin), and small molecules used to treatcancer (e.g., vincristine, vinblastin, paclitaxel, docetaxel, cisplatin,irinotecan, topotecan, gemcitabine, temozolomide, imatinib, bortezomib),statins (e.g., atorvastatin, amlodipine, rosuvastatin, sitagliptin,simvastatin, fluvastatin, pitavastatin, lovastatin, pravastatin,simvastatin), and other taxane derivatives. In particular embodiments,the small molecules that can be used include those that treattuberculosis (e.g., rifampicin), small molecule anti-fungal agents(e.g., fluconazole), small molecule anti-anxiety agents and smallmolecule anti-convulsant agents (e.g. lorazepam), small moleculeanti-cholinergic agents (e.g., atropine), small molecule β-agonist drugs(e.g., albuterol sulfate), small molecule mast cell stabilizers andsmall molecule agents used to treat allergies (e.g. cromolyn sodium),small molecule anesthetic agents and small molecule anti-arrhythmicagents (e.g., lidocaine), small molecule antibiotic agents (e.g.tobramycin, ciprofloxacin), small molecule anti-migraine agents (e.g.,sumatriptan), and small molecule anti-histamine drugs (e.g.,diphenhydramine). Further, the amount of the small molecule drugs in thedosage formulations can be varied depending on current acceptableamounts, subject/patient needs, and the like. With respect to thebiocompatible non-aqueous solvent, examples include aprotic polarsolvents, alkyl or aryl benzoate solvents, lipid solvents, proticsolvents, or a mixture thereof. Non-limiting examples of aproticsolvents include dimethylsulfoxide (DMSO), dimethylformamide (DMF),ethyl acetate, n-methylpyrrolidone (NMP), dimethyl acetamide (DMA),propylene carbonate, or mixtures thereof. In some instances, however,the formulations of the present invention do not have to include theaforementioned solvents (i.e., others can be used). In one instance, forexample, the formulations do not include non-aqueous aprotic polarsolvents and/or do not include non-aqueous protic solvents (e.g.,polyethylene glycol (PEG), propylene glycol (PG), polyvinylpyrrolidone(PVP), methoxypropylene glycol (MPEG), glycerol, glycofurol, andmixtures thereof). As noted above, the increased solubility of the smallmolecule drugs can result in small dosage volumes (and, in turn, smallstorage devices and containers), which provides for an easier and lesspainful administration parenterally. Non-limiting examples of aryl oralkyl benzoate solvents include methyl benzoate, ethyl benzoate, propylbenzoate, C12-C15 alkyl benzoates, in which R is a C12-15 alkyl group,C16-17 alkyl benzoate, in which R is a C16-17 fatty alcohol group, andbenzyl benzoate. A non-limiting example of a lipid is triacetin, whichis the triester of glycerol and acetic acid. Non-limiting examples ofprotic solvents include polyethylene glycol (PEG), propylene glycol(PG), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG),glycerol, glycofurol, or mixtures thereof. In certain aspects, theformulation does not include a co-solvent, while in other aspects it caninclude a co-solvent. In one instance, the formulation can include asingle/only one biocompatible non-aqueous solvent (i.e., in neat or pureform). In other aspects, the formulation includes a mixture of two,three, four, or more biocompatible non-aqueous solvents. In stilladditional aspects, the formulation can exclude co-solvents, salts, andother ingredients that can help with or increase the solubility of thesmall molecule drug in the non-aqueous solvent. For instance, theformulation can consist of or consist essentially of a small moleculedrug and a non-aqueous solvent (or mixture of non-aqueous solvents) andstill be directly injected through parenteral administration to asubject (with consist essentially of meaning in the context of thissentence exclusion of other ingredients that could increase thesolubility of the drug within the non-aqueous solvent (or mixture ofnon-aqueous solvents—e.g., a preservative can be included to furtherpreserve the injectible formulation). Further, the formulation of thepresent invention can be non-aqueous or substantially non-aqueous (e.g.,less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less of waterby weight or volume). In some instances, the small molecule drug haspreviously been dried in the presence of a buffer prior to beingsolubilized in the non-aqueous solvent. As explained below, this can addto the stability of the small molecule drug. In some instances, thedried small molecule drug has a pH memory that is about equal to the pHof the small molecule drug in the presence of the aqueous buffer suchthat the pH of the small molecule drug that is solubilized in thebiocompatible non-aqueous solvent is about equal to the pH of the smallmolecule drug in the presence of the buffer. The memory pH can be 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, or more or can be a range of 1 to 3, 2 to4, 3 to 5, 4 to 6, 5 to 7, 6 to 8, 7 to 9, 8 to 10 or 9 to 11. Incertain aspects, the buffer is a non-volatile buffer (non-limitingexamples of which include glycine buffers, citrate buffers, or phosphatebuffers, or a mixture thereof). In other instances, the buffer can be avolatile buffer. Further, the water content of the small molecule drugcan be less than 5%, 4%, 3%, 2%, 1%, 0.5% or less w/w. In certainaspects, the formulation includes from 0.5 mg/mL to about 300 mg/mL, 10mg/mL to 50 mg/mL, 20 mg/mL to 50 mg/mL, 5 mg/mL to 15 mg/mL, or 0.5mg/mL to 2 mg/mL of the small molecule drug. In some instances, theamount of the small molecule drug can be as high as 400, 500, 600, 700,800, 900, 1000, 2000, or 3000 mg/mL or more. One of the unique aspectsof the present formulation is that the formulation can have a highcontent of the drug, yet the dosage amount of the formulation can berelatively low (e.g., 0.1 μl, 1 μl, 10 μl, 20 μl, 50 μl, 75 μl, 100 μl,200 μl, 300 μl, 400 μl, 500 μl, 600 μl, 700 μl, 800 μl, 900 μl, 1 ml, 2ml, or 3 ml, or more as needed (e.g., 4, 5, 6, 7, 8, 9, 10 ml or more).In certain instances, the volume of the liquid formulation to beparenterally injected is 3 ml or less (e.g., 3, 2.5, 2, 1.5, 1, 0.5, 0.1ml or less) or is from 0.1 μl to 3 ml or from 0.1 μl to 1 μl or from 1μl to 10 μl or from 10 μl to 1 ml or from 0.1 μl to 2.5 ml or from 0.1μl to 2 ml or from 0.1 μl to 1.5 ml or from 0.1 μl to 1 ml or from 0.1μl to 0.5 ml or from 0.1 μl to 0.1 ml. Another unique aspect of thepresent formulation is that it can be contained in a container ordevice, be stored, and be immediately ready for parenteral injection onan as needed basis without having to reconstitute or dilute theformulation. The device can be a syringe, a pen injection device, anauto-injector device, a device that can pump or administer theformulation (e.g., automatic or non-automatic external pumps,implantable pumps, etc.) or a perfusion bag. Also contemplated for usein the formulations are additional ingredients/pharmaceuticalexcipients, non-limiting example of which include: antioxidants(examples include ascorbic acid, cysteine, methionine, monothioglycerol,sodium thiosulfate, sulfites, BHT, BHA, ascorbyl palmitate, propylgallate, or vitamin E); chelating agents (examples include EDTA, EGTA,tartaric acid, glycerin, or citric acid); or preservatives (examplesinclude alkyl alcohols, benzyl alcohol, a methyl paraben, or a propylparaben or mixtures thereof). The formulation can be in liquid form,semi-solid form, or gel form. As discussed below, the formulation canhave a desired viscosity range (in one non-limiting example, such arange could be between 0.5 to 15 cps). The formulation can be such thatat least 65% of the small molecule drug within the formulation remainschemically and physically stable when the formulation is stored at roomtemperature for two months or at least 80% of the therapeutic agentwithin the formulation remains chemically and physically stable when theformulation is stored at room temperature for two months.

In one particular aspect of the present invention, there is disclosed astable liquid formulation for parenteral injection comprising diazepam,or a salt thereof that has a water content of less than 1% w/w and abiocompatible non-aqueous solvent, wherein the diazepam is solubilizedwithin the non-aqueous solvent, wherein the water content of theformulation is less than 5% w/v, wherein the volume of the formulationto be parenterally injected is between 50 μl to 1000 μl or any rangetherein (e.g., 75 μl, 100 μl, 150 μl, 200 μl, 300 μl, 400 μl, 500 μl,600 μl, 700 μl, 800 μl, 900 μl, etc.). As explained above, such aformulation can be comprised in a container selected from the group cona sealed syringe, a sealed pen injection device, a sealed auto-injectordevice, or a pump. Also as explained above, the diazepam can be beendried in the presence of a buffer prior to being solubilized in thenon-aqueous solvent. This can provide the dried diazepam with a pHmemory that is about equal to the pH of diazepam in the presence of theaqueous buffer such that the pH of the diazepam that is solubilized inthe biocompatible non-aqueous solvent is about equal to the pH of thediazepam in the presence of the aqueous buffer (e.g., the aforementionednon-volatile buffers such as glycine buffers, citrate buffers, orphosphate buffers, or a mixture thereof).

Also disclosed is a method of administering the formulations of thepresent invention by parenteral administration of the formulation to asubject in need thereof. The administration can be performed withouthaving to reconstitute and/or dilute the formulation. Further, theadministration can be performed with a syringe, a pen injection device,an auto-injector device, a pump, or a perfusion bag. Also, theformulation can be stored in said syringe, pen injection device,auto-injector device, pump, or perfusion bag, which can then beimmediately used (again without having to reconstitute and/or dilute theformulation). Further, and as noted above, the amount of the formulationbeing administered can range from 1 μl, 10 μl, 20 μl, 50 μl, 75 μl, 100μl, 200 μl, 300 μl, 400 μl, 500 μl, 600 μl, 700 μl, 800 μl, 900 μl, 1ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, or 10 ml, or more asneeded. In certain aspects, the formulations are such that the smallmolecule drug remains stable and solubilized (i.e., no coalescence orcrystallization of the small molecule drug) and when stored at roomtemperature (approximately 20-25° C.) for at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 months.

In a further aspect of the present invention there is disclosed a methodfor treating or preventing a condition, disease, disorder, etc.comprising administering to a subject in need thereof any one of theformulations of the present invention in an amount effective to treat orprevent the condition, disease, disorder, etc. For instance, and withrespect to the aforementioned diazepam formulation, such formulationscan be used to treat epileptic seizure, especially severe seizures in anemergency situation. In this instance, the method can includeadministering to the subject in need thereof a soluble and stablediazepam formulation of the present invention in an amount effective totreat the seizure. The aforementioned administration techniques can beused (e.g., parenterally, pre-loaded containers, etc.). In some aspects,the condition can be anxiety, muscle spasms, or seizures (e.g.,epileptic seizure).

Also contemplated is a method of the stable formulations of the presentinvention. The method can include obtaining a small molecule drug andadding one or more biocompatible non-aqueous solvents in an amount tosufficient dissolve the small molecule drug in the solvent. The methodcan further include storing the formulation in a container such as avial or in a syringe, a pen injection device, an auto-injector device, apump, or a perfusion bag. The process can further include drying thesmall molecule drug in the presence of a buffer prior to adding in thenon-aqueous solvent(s). In a broader aspect, the process can be appliedto formulate any small molecule drug that has limited or poor solubilityor stability in an aqueous environment.

As briefly mentioned above, it is also contemplated that the viscosityof the formulations can be selected to achieve a desired result, e.g.,depending on the type of composition desired, the route ofadministration, and the like. In one instance, the viscosity of theformulations can be from about 0.5 cps to well over 1 million cps or anyrange or integer derivable therein (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800,900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 20000,30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 200000, 300000,400000, 500000, 600000, 700000, 800000, 900000, 1000000 cps, etc., asmeasured on a Brookfield Viscometer using a TC spindle at 2.5 rpm at 25°C.). In particular aspects, however, a viscosity range between 0.5 cpsto about 100 cps or about 0.5 cps to about 15 cps can be used.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method or composition of theinvention, and vice versa. Furthermore, compositions of the inventioncan be used to achieve methods of the invention.

“Aprotic polar solvent” means a polar solvent that does not containacidic hydrogen and does not act as a hydrogen bond donor. Examples ofpolar aprotic solvents include dimethylsulfoxide (DMSO),dimethylformamide (DMF), ethyl acetate, n-methylpyrrolidone (NMP),dimethylacetamide (DMA) and propylene carbonate.

“Alkyl or aryl benzoates” refers to the following compound:

where R is an alkyl or aryl group. Examples of alkyl benzoates includemethyl benzoate, ethyl benzoate, propyl benzoate, C12-C15 alkylbenzoates, in which R is a C12-15 alkyl group, and C16-17 alkylbenzoate, in which R is a C16-17 fatty alcohol group. A non-limitingexample of aryl benzoate includes benzyl benzoate.

“Parenteral injection” refers to the administration of small moleculedrugs via injection under or through one or more layers of skin or mucusmembranes of an animal, such as a human. Standard parenteral injectionsare given into the subcutaneous, intramuscular, or intradermal region ofan animal, e.g., a human patient. These deep locations are targetedbecause the tissue expands more easily, relative to shallow dermalsites, to accommodate the 0.1-3.0 cc (mL) injection volumes required todeliver most therapeutic agents.

“Pharmaceutically acceptable carrier” means a pharmaceuticallyacceptable solvent, suspending agent or vehicle for delivering a drugcompound of the present invention to a mammal such as an animal orhuman.

“Pharmaceutically acceptable” ingredient, excipient or component is onethat is suitable for use with humans and/or animals without undueadverse side effects (such as toxicity, irritation and allergicresponse) commensurate with a reasonable benefit/risk ratio.

“Chemical stability” means that with respect to the small molecule drug,an acceptable percentage of degradation products produced by chemicalpathways such as oxidation or hydrolysis is formed. In particular, aformulation is considered chemically stable if no more than about 20%breakdown products are formed after one year of storage at the intendedstorage temperature of the product (e.g., room temperature); or storageof the product at 30° C./60% relative humidity for one year; or storageof the product at 40° C./75% relative humidity for one month, andpreferably three months, and more preferably six months.

“Physical stability” means that with respect to the small molecule drug,an acceptable percentage of crystals or other aggregates (e.g., dimers,trimers, etc.) is formed. In particular, a formulation is consideredphysically stable if no more that about 15% aggregates are formed afterone year of storage at the intended storage temperature of the product(e.g., room temperature); or storage of the product at 30° C./60%relative humidity for one year; or storage of the product at 40° C./75%relative humidity for one month, and preferably three months, and morepreferably six months.

“Stable formulation” means that at least about 65% chemically andphysically stable small molecule drug remains after two months ofstorage at room temperature. In some aspects, the formulations retain atleast about 80% chemically and physically stable small molecule drugunder these conditions. Even further, some stable formulations are thosewhich do not exhibit degradation after sterilizing irradiation (e.g.,gamma, beta or electron beam).

“Bioavailability” refers to the extent to which the small molecule drugis absorbed from the formulation by the subject.

“Systemic” means, with respect to delivery or administration of a smallmolecule drug to a subject, that therapeutic agent is detectable at abiologically significant level in the blood plasma of the subject.

“Controlled-release” refers to the release of the small molecule drug atsuch a rate that blood (e.g., plasma) concentrations are maintainedwithin the therapeutic range, but below toxic concentrations over aperiod of time of about one hour or longer, preferably 12 hours orlonger.

“Patient,” “subject,” or “individual” refers to a mammal (e.g., human,primate, dog, cat, bovine, ovine, porcine, equine, mouse, rate, hamster,rabbit, or guinea pig).

“Inhibiting” or “reducing” or any variation of these terms, when used inthe claims and/or the specification includes any measurable decrease orcomplete inhibition to achieve a desired result.

“Effective” or “treating” or “preventing” or any variation of theseterms, when used in the claims and/or specification, means adequate toaccomplish a desired, expected, or intended result.

The term “about” or “approximately” are defined as being close to asunderstood by one of ordinary skill in the art, and in one non-limitingembodiment the terms are defined to be within 10%, preferably within 5%,more preferably within 1%, and most preferably within 0.5%. Further,“substantially non-aqueous” refers to less than 5%, 4%, 3%, 2%, 1%, orless by weight or volume of water.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.”

The words “comprising” (and any form of comprising, such as “comprise”and “comprises”), “having” (and any form of having, such as “have” and“has”), “including” (and any form of including, such as “includes” and“include”) or “containing” (and any form of containing, such as“contains” and “contain”) are inclusive or open-ended and do not excludeadditional, unrecited elements or method steps.

The compositions and methods for their use can “comprise,” “consistessentially of,” or “consist of” any of the ingredients or stepsdisclosed throughout the specification. With respect to the transitionalphase “consisting essentially of,” in one non-limiting aspect, a basicand novel characteristic of the formulations and methods disclosed inthis specification includes the stability and solubility of the smallmolecule drugs within said formulations. Therefore, ingredients that cannegatively or positively affect the stability or solubility of the smallmolecule drugs within the formulations would be excluded from saidformulations in instances where a claim uses the transitional phrase“consisting essentially of.”

Other objects, features and advantages of the present invention willbecome apparent from the following detailed description. It should beunderstood, however, that the detailed description and the examples,while indicating specific embodiments of the invention, are given by wayof illustration only. Additionally, it is contemplated that changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: Plasma diazepam levels in rats after administration of 1 mgdiazepam as subcutaneous injections of XeriSol™ diazepam in theindicated solvents or as Diastat rectal gel. Curves represent 5 animalsper group except as otherwise noted.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

As discussed above, the difficulties associated with formulating smallmolecule drugs for parenteral administration are well-documented. Thecurrent solutions to such difficulties are also well-documented andaccepted as standard practice in the formulations field. Briefly, theproblems begin with the desire to create aqueous formulations for smallmolecule drugs that would be well-tolerated and dispersible within thebody (and in particular, the blood stream) despite the fact that mostsmall molecule drugs have low solubility and stability in aqueousenvironments. This typically results in the use of co-solvents and drugstability agents, which can result in large and/or multiple dosages(e.g., upwards of 3 mL) to ensure that a sufficient amount of the drugis administered. Further, the added steps of reconstitution and/ordilution prior to injection can be costly and time consuming.

To address the current issues associated with parenteral administrationof small molecule drugs, the inventors offer a unique approach that goesagainst the well-accepted and traditional formulation standards. Inparticular, the inventors have discovered that by solubilizing a smallmolecule drug in a non-aqueous environment, the resulting formulation isnot only highly concentrated with the drug (which then leads to a lowerdosage volume of the formulation), it also provides for increasedstability and solubility of said drug. This in-turn leads to a morestable formulation that enjoys a longer shelf/storage life that can bedirectly injected into a subject without the use of a reconstitution ordilution step. Thus, the formulations of the present invention can bestored in a device that can immediately be used for parenteraladministration.

These and other non-limiting aspects of the present invention arediscussed below.

A. Small Molecule Drugs

“Small molecule drugs” in the context of the present invention arebiologically active compounds (and salts thereof) that can bring about adesired, beneficial, and/or pharmacological effect on a subject. These“small molecule drugs” are organic or inorganic compounds, but they arenot polymers (e.g., peptides, proteins, polypeptides, carbohydrates, andnucleic acids). Therefore, the small molecule drugs in the context ofthe present invention are not polymeric compounds. Typically, the smallmolecule drugs have a molecular weight of less than approximately 1000Daltons. Certain small molecule drugs are “moisture sensitive” in thatthey are increasingly unstable in the presence of water. Also, saltsthat can be used with the small molecule drugs are known to thoseskilled in the art and include salts with inorganic acids, organicacids, inorganic bases, or organic bases.

Non-limiting examples of a few classes of small molecule drugs that canbe used in the context of the present invention include benzodiazepines,catecholemines, and “triptans.” As noted in the examples, one such drugdiazepam, has been shown to work well in the context of the presentinvention as evidenced by its increased stability and solubility in anon-aqueous solvent. Other non-limiting examples include epinenpherine,sumatriptan, novantrone, chemotherapy small molecules (e.g.,mitoxantrone), corticosteroid small molecules (e.g., methylprednisolone,beclomethasone dipropionate), immunosuppressive small molecules (e.g.,azathioprine, cladribine, cyclophosphamide monohydrate, methotrexate),anti-inflammatory small molecules (e.g., salicylic acid, acetylsalicylicacid, diflunisal, choline magnesium trisalicylate, salicylate,benorylate, flufenamic acid, mefenamic acid, meclofenamic acid,triflumic acid, diclofenac, fenclofenac, alclofenac, fentiazac,ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, fenbufen,suprofen, indoprofen, tiaprofenic acid, benoxaprofen, pirprofen,tolmetin, zomepirac, clopinac, indomethacin, sulindac, phenylbutazone,oxyphenbutazone, azapropazone, feprazone, piroxicam, isoxicam), smallmolecules used to treat neurological disorders (e.g., cimetidine,ranitidine, famotidine, nizatidine, tacrine, donepizil, metrifonate,rivastigmine, selegilene, imipramine, fluoxetine, olanzapine,sertindole, risperidone, valproate semisodium, gabapentin,carbamazepine, topiramate, phenyloin), small molecules used to treatcancer (e.g., vincristine, vinblastin, paclitaxel, docetaxel, cisplatin,irinotecan, topotecan, gemcitabine, temozolomide, imatinib, bortezomib),statins (e.g., atorvastatin, amlodipine, rosuvastatin, sitagliptin,simvastatin, fluvastatin, pitavastatin, lovastatin, pravastatin,simvastatin), and other taxane derivatives, small molecules used totreat tuberculosis (e.g., rifampicin), small molecule anti-fungal agents(e.g., fluconazole), small molecule anti-anxiety agents and smallmolecule anti-convulsant agents (e.g., lorazepam), small moleculeanti-cholinergic agents (e.g., atropine), small molecule f3-agonistdrugs (e.g., albuterol sulfate), small molecule mast cell stabilizersand small molecule agents used to treat allergies (e.g., cromolynsodium), small molecule anesthetic agents and small moleculeanti-arrhythmic agents (e.g., lidocaine), small molecule antibioticagents (e.g., tobramycin, ciprofloxacin), small molecule anti-migraineagents (e.g., sumatriptan), and small molecule anti-histamine drugs(e.g., diphenhydramine).

Each of the aforementioned drugs are well-known and commerciallyavailable from a wide variety of sources. Further, the amount of thesmall molecule drugs in the dosage formulations can be varied dependingon current acceptable amounts, subject/patient needs (e.g., age, health,weight, nature and extend of symptom), and the like. What is unique inthe context of the present invention is the fact that the dosage volumescan be decreased, and concentrated liquid preparations of the compoundscan be pre-made and stored, given the increased solubility and stabilityof the small molecule drugs within the formulations of the presentinvention.

B. Biocompatible Non-Aqueous Solvents

“Biocompatible non-aqueous solvent” in the context of the presentinvention refers to a solvent that is substantially to completely devoidof water and is capable of solubilizing a small molecule drug. Thesolvent is also biocompatible in that it is suitable for use with humanor animals without undue adverse side effects (such as toxicity,irritation, and allergic response) commensurate with a reasonablebenefit/risk ratio.

Non-limiting examples of some suitable biocompatible, non-aqueoussolvents include aprotic polar solvents, alkyl or aryl benzoates, andlipids. Examples of polar aprotic solvents include dimethylsulfoxide(DMSO), dimethylformamide (DMF), ethyl acetate, n-methyl pyrrolidone(NMP), dimethylacetamide (DMA), propylene carbonate, and mixturesthereof. Non-limiting examples of alkyl benzoates include methylbenzoate, ethyl benzoate, propyl benzoate, C12-C15 alkyl benzoates, inwhich R is a C12-15 alkyl group, and C16-17 alkyl benzoate, in which Ris a C16-17 fatty alcohol group. A non-limiting example of aryl benzoateincludes benzyl benzoate. A non-limiting example of a lipid istriacetin, which is the triester of glycerol and acetic acid.

Each of the aforementioned non-aqueous solvents are well-known andcommercially available from a wide variety of sources.

C. pH Memory

In addition to the non-aqueous solvent aspect of the present invention,the inventors also discovered a further processing step that can be usedto further stabilize the small molecule drug within the formulation. Inparticular, a small molecule drug can be mixed with a non-volatilebuffer, and then dried to obtain a small molecule drug powder. Drugs aresusceptible to hydrolysis at certain bonds, so the use of non-volatilebuffers in the formulations of the present invention are believed tobeneficially affect their chemical stability. The result of this processstep is the production of a “pH memory” of the small molecule drug afterit is reconstituted in then non-aqueous solvent.

In particular, the “pH memory” of small molecule drug is the resultingcharge profile (protonation state) after drying the drug from a bufferedaqueous solution (e.g., from a non-volatile buffer). The protonationstate, and thus the solubility and stability of the drug, in very low orzero moisture non-aqueous solvents are affected by the aqueous pH of thedrug solution before drying and the drying conditions employed.Similarly, the stability of uncharged drugs is impacted by pH in aqueoussolutions, and thus, pH memory in a dried state or in a non-aqueoussolvent. When the drug is dried in a buffer species in which both theacidic and basic components are non-volatile, the pH memory of the drieddrug will be about equal to the pH of the drug in the non-volatilebuffer. See, e.g., Enzymatic Reactions in Organic Media, Koskinen, A. M.P., and Klibanov, A. M., eds., Springer (1996). Furthermore, the pH ofthe buffered aqueous solution (e.g., non-volatile buffer) in which thedrug is dried can be optimized to yield a pH memory for the drug thatresults in optimal drug stability, maximum solubility, and minimaldegradation when the dried drug is subsequently reconstituted in thenon-aqueous solvent (e.g., aprotic polar solvent). It should be notedthat many non-aqueous solvents do not have exchangeable protons.Therefore, when a dried drug is reconstituted into such a solvent, thedrug in the reconstituted formulation will maintain the solubility andstability characteristics of the optimal pH memory. In particularembodiments, the drug in the formulation will have a pH memory of about2.0 to 3.0 to ensure maximal stability/minimal degradation. In otherembodiments, the drug in the formulation will have a pH memory of about3.0 to 5.0 to ensure maximal stability/minimal degradation. In yet otherembodiments, the drug will have a pH memory of about 4.0 to 6.0 toensure maximal stability/minimal degradation. In yet other embodiments,the drug will have a pH memory of about 6.0 to 11.0 to ensure maximalstability/minimal degradation.

The pH memory of a drug can be measured in several ways. In one method,the pH memory of a drug is measured by reconstituting the dried druginto un-buffered water and measuring the pH of the reconstituted drugwith a pH indicator such as pH paper or a calibrated pH electrode.Alternatively, the pH memory of a drug can be determined for a drug thathas been reconstituted in a non-aqueous solvent by adding at least 20%water to the non-aqueous solvent and measuring the pH with a pHindicator. See, e.g., Baughman and Kreevoy, “Determination of Acidity in80% Dimethyl Sulfoxide-20% Water,” Journal a/Physical Chemistry,78(4):421-23 (1974). Measurement of pH in an aprotic polar solvent-watersolution may require a small correction (i.e., no more than 0.2 pH unitas per Baughman and Kreevoy, supra).

In view of the above, non-volatile buffers that are useful in theformulations described herein are those that are helpful in establishinga pH of maximum stability/minimal degradation as well as those that arehelpful in removing residual water content from the dried drug powder.Nonvolatile buffers include those buffers that will not evaporate awayin a manner similar to water upon drying/lyophilization. Suitablenonvolatile buffers include, for example, glycine buffers, citratebuffers and phosphate buffers. In one preferred embodiment, thenonvolatile buffer is a glycine buffer or a citrate buffer.

In the foregoing process, drying of the drug compound with thenonvolatile buffer can be carried out using spray-drying techniques,freeze-drying techniques or lyophilization techniques. Spray dryingtechniques are well known to those skilled in the art. Spray dryingincludes the steps of atomization of a solution containing one or moresolids (e.g., therapeutic agent) via a nozzle spinning disk, or otherdevice, followed by evaporation of the solvent from the droplets. Thenature of the powder that results is the function of several variablesincluding the initial solute concentration, size distribution ofdroplets produced and the rate of solute removal. The particles producedmay comprise aggregates of primary particles which consist of crystalsand/or amorphous solids depending on the rate and conditions of solventremoval.

A spray-drying process for preparing ultra-fine powders of drugs isdescribed, for example, in U.S. Pat. No. 6,051,256. Freeze-dryingprocedures are well known in the art, and are described, for example, inU.S. Pat. Nos. 4,608,764 and 4,848,094. Spray-freeze-drying processesare described, for example, in U.S. Pat. No. 5,208,998. Otherspray-drying techniques are described, in U.S. Pat. Nos. 6,253,463;6,001,336; 5,260,306; and PCT International Publication Nos. WO91/16882and WO 96/09814.

Lyophilization techniques are well known to those skilled in the art.Basically, lyophilization is a dehydration technique that takes placewhile a product is in a frozen state and under a vacuum (ice sublimationunder a vacuum) and drying by gentle heating. These conditions stabilizethe product, and minimize oxidation and other degradative processes. Theconditions of freeze drying permit running the process at lowtemperatures, therefore, thermally labile products can be preserved.Steps in freeze drying include pretreatment, freezing, primary dryingand secondary drying. Pretreatment includes any method of treating theproduct prior to freezing. This may include concentrating the product,formulation revision (i.e., addition of components to increase stabilityand/or improve processing), decreasing a high vapor pressure solvent orincreasing the surface area. Methods of pretreatment include: freezeconcentration, solution phase concentration, and formulatingspecifically to preserve product appearance or to provide lyoprotectionfor reactive products, and are described, e.g., in U.S. Pat. No.6,199,297. “Standard” lyophilization conditions, are described, e.g., inU.S. Pat. No. 5,031,336, and in “Freeze Drying of Pharmaceuticals”(DeLuca, Patrick P., J. Vac. Sci. Technol., Vol. 14, No. 1,January/February 1977); and “The Lyophilization of Pharmaceuticals: ALiterature Review” (Williams, N. A., and G. P. Polli, Journal ofParenteral Science and Technology, Vol. 38, No. 2, March/April 1984).

In certain aspects, the lyophilization cycle can be partially performedabove the glass transition temperature (Tg) of the therapeutic agentformulation to induce a collapse of the mass to form a dense cakecontaining residual water. In other embodiments, the lyophilizationcycle is carried out below the glass transition temperature in order toavoid a collapse in order to achieve a complete drying of the particles.

D. Moisture Content of Formulations

An additional key aspect of the formulations of the present invention isthat they have a low moisture content by virtue of using the previouslydescribed non-aqueous solvents. This provides for additional stabilityof both the formulation and the small molecule drug. For instance, thestable formulations of the present invention can have a moisture contentthat is less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%,0.1%, 0.05%, 0.025%, 0.01%, to 0% by weight or volume of theformulation. In some instances, the formulation includes from about0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% toabout 1.5% or from about 0.01% to about 1% by weight or volume of waterin the formulation.

E. Dosages

Any suitable dosage of drugs can be administered using the formulationsof the present invention. The dosage administered will, of course, varydepending upon known factors, such as: the pharmacodynamiccharacteristics of the particular drug, salt, or combination thereof;the age, health, or weight of the subject; the nature and extent ofsymptoms; the metabolic characteristics of the therapeutic agent andpatient, the kind of concurrent treatment; the frequency of treatment;or the effect desired. Generally, the drug is present in the formulationin an amount ranging from about 0.5 mg/mL to about 3000 mg/mL or up tothe solubility limit of the drug in the formulation. In someembodiments, the drug is present in the formulation in an amount rangingfrom about 10 mg/mL to about 50 mg/mL. In other embodiments, the drug ispresent in the formulation in an amount ranging from about 20 mg/mL toabout 50 mg/mL. In still other embodiments, the drug is present in saidformulation in an amount ranging from about 5 mg/mL to about 15 mg/mL.In yet other embodiments, the drug is present in the formulation in anamount ranging from about 0.5 mg/mL to about 2 mg/mL. Again, it will bereadily apparent to those of skill that the drug dosage can be varieddepending on the drug used and the disease, disorder or condition to betreated, and the concentration of the drug in the formulation will varydepending on the drug solubility, dosage, and method of administration.

F. Additional Ingredients/Pharmaceutical Excipients

While the formulations of the present invention are sufficient anduseful with a small molecule drug and a biocompatible non-aqueoussolvent (see Example 1, Tables 1-2), the formulation can includeadditional ingredients/pharmaceutical excipients to further develop aformula to have a desired tactile property, viscosity range, or tofurther protect the drug active. For instance, the formulations canfurther include any one of, any combination of, or all of an antioxidant(non-limiting examples of which include ascorbic acid, cysteine,methionine, monothioglycerol, sodium thiosulfate, sulfites, BHT, BHA,ascorbyl palmitate, propyl gallate, or vitamin E or any combinationthereof); a chelating agent (non-limiting examples of which includeEDTA, EGTA, tartaric acid and salts thereof, glycerin, and citric acidand salts thereof); and/or a preservative (non-limiting examples ofwhich include alkyl alcohols, benzyl alcohols, methyl parabens, propylparabens and mixtures thereof). Further, the formulations of the presentinvention can also include a non-aqueous protic solvent (non-limitingexamples of which include polyethylene glycol (PEG), propylene glycol(PG), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG),glycerol, glycofurol, and mixtures thereof).

G. Kits/Containers

Kits are also contemplated as being used in certain aspects of thepresent invention. For instance, a formulation of the present inventioncan be included within a kit. A kit can include a container. In oneaspect, for instance, the formulation can be comprised within acontainer that is ready to parenterally administer to a subject withouthaving to reconstitute or dilute the formulation. That is, theformulation to be administered can be stored in the container and bereadily used as needed. The container can be a device. The device can bea syringe, a pen injection device, an auto-injector device, a devicethat can pump or administer the formulation (e.g., automatic ornon-automatic external pumps, implantable pumps, etc.) or a perfusionbag. Suitable pen/auto-injector devices include, but are not limited to,those pen/auto-injection devices manufactured by Becton-Dickenson,Swedish Healthcare Limited (SHL Group), YpsoMed Ag, and the like.Suitable pump devices include, but are not limited to, those pumpdevices manufactured by Tandem Diabetes Care, Inc., DelsysPharmaceuticals and the like.

Alternatively, a kit of the present invention can include multiplecontainers or multiple compartments within a container. Each containeror multiple compartments can be used to store, for instance, thebiocompatible non-aqueous solvent and the small molecule drugseparately. Then, as needed, the solvent and drug can be mixed togetherand administered immediately or stored for a later time, as needed.

EXAMPLES

The present invention will be described in greater detail by way ofspecific examples. The following examples are offered for illustrativepurposes, and are not intended to limit the invention in any manner.Those of skill in the art will readily recognize a variety ofnoncritical parameters which can be changed or modified to yieldessentially the same results.

Example 1 Solubility and Stability of Diazepam in BiocompatibleNon-Aqueous Solvents

Diazepam, a small molecule anti-anxiety/anti-convulsant drug (MW=284.7g/mol; anhydrous, Sigma-Aldrich, St. Louis, Mo.) powder was mixed withvarious biocompatible, non-aqueous solvents in 50 mg increments until itno longer dissolved. The maximum solubility of diazepam at thisresolution was thus determined, and is reported in Table 1, along withthe corresponding injection volume of a 20-mg dose at theseconcentrations.

TABLE 1 Solubility Injection Solvent (mg/ml) Solubility Volume, μl (20mg) NMP 535 Freely Soluble 37.4 DMSO 125 Freely Soluble 160 70:30  100*Freely Soluble 200 DMSO:NMP Benzyl benzoate 125 Freely Soluble 160Triacetin  50 Soluble 400 PEG 300  50 Soluble 400 *Highest concentrationtested. Based on diazepam solubility in DMSO and NMP alone, this valueis expected to be at least 125 mg/ml.

Table 2 provides definitions for solubility used in Table 1 and in thefollowing tables.

TABLE 2 Parts of Solvent Solubility Range Solubility per 1 Part Solute(g/ml) (mg/ml) Very Soluble <1 >1 >1000 Freely Soluble 1-10  0.1-1.0100-1000 Soluble 10-30  0.03-0.1 30-100 Sparingly Soluble 30-100 0.01-0.03 10-30  Slightly Soluble 100-1000 0.001-0.01 1-10 VerySlightly 1000-10000 0.0001-0.001 0.1-1   Soluble Practically >10000<0.0001 <0.1 Insoluble or Insoluble

Diazepam solutions were prepared at various concentrations and evaluatedfor stability over one or six months. Solutions in Table 3 were preparedby diluting solubility test samples and were stored in glass vials atambient conditions, and solutions in Table 4 were prepared using thefollowing process and stored in syringes in stability chambers:

-   -   (1) Prepare any blended solvents (e.g., 70:30 DMSO:NMP) in their        indicated proportions (v/v) and mix.    -   (2) Weigh a mass of diazepam powder appropriate for final        concentration of 50 or 100 mg/mL.    -   (3) Dissolve diazepam powder in approximately 70% final volume        solvent in glass volumetric flask fitted with ground glass        stopper.        -   (a) Stir or sonicate solution.        -   (b) Requires less than 20 minutes dissolution time.    -   (4) Add solvent complement to bring to final solution volume.    -   (5) Stopper the flask and mix end-over-end at least 10 times.    -   (6) Verify drug content and purity via RP-HPLC.        All prepared solutions remained clear by visual inspection and        no crystals were observed by light microscopy under 100×        magnification in the highest concentration solutions presented        in Table 3 after 10 days. Drug content and purity were evaluated        using a verified USP RP-HPLC method. The absence of particulates        was evaluated using visible light spectroscopy to measure        transmittance at 630 nm. These data are detailed in Tables 3 and        4.

TABLE 3 Solvent (Diazepam % Purity % Concentration, Two Transmittancemg/ml) Weeks Three Weeks One Month One Month NMP 99.73/NA/ 99.84/99.85/99.87/99.88/ NA/100/99.8 (200/100/50) NA 99.86 99.9 DMSO 99.81/NA/99.76/99.79/ 99.8/99.83/ 99.5/NA/100 (125/100/50) NA 99.80 99.85 Benzyl99.89/NA/ 99.88/99.90/ 99.91/99.91/ 100/99.8/100 Benzoate NA 99.85 99.86(125/100/50) 70:30 NA 99.78 99.87 99.5 DMSO:NMP (50)

TABLE 4 25° C./60% Relative Humidity 40° C./75% Relative Humidity ActualActual Diazepam Months Diazepam % % Diazepam % Formulation Concentrationof Concentration Drug % Transmittance Concentration Drug % % Solution(mg/ml) Stability (mg/ml) Content Purity (630 nm) (mg/ml) Content PurityTransmittance DMSO 50 T = 0 51.5 103.0% 100.00% 99.8 51.5 103.0% 100.00%99.8 One 48.9 97.8% 99.88% 99.8 50.8 101.6% 99.47% 100.0 Three 50.9101.7% 100.00% 100.0 49.2 98.3% 100.00% 100.0 Six 48.2 96.3% 100.00%100.0 48.9 97.8% 100.00% 100.0 100 T = 0 102.4 102.4% 100.00% 99.8 102.4102.4% 100.00% 99.8 One 99.6 99.6% 99.86% 100.0 99.2 99.2% 99.63% 100.0Three 99.7 99.7% 100.00% 99.8 98.7 98.7% 99.99% 99.8 Six 98.7 98.7%100.00% 99.8 81.0 81.0% 100.00% 100.0 NMP 50 T = 0 51.1 102.1% 99.80%100.0 51.1 102.1% 99.80% 100.0 One 50.4 100.8% 99.97% 100.2 50.9 101.8%99.95% 100.0 Three 50.5 101.0% 99.97% 100.0 50.1 100.1% 99.94% 100.0 Six50.4 100.8% 99.94% 100.0 101.6 101.6% 99.96% 100.0 100 T = 0 104.3104.3% 100.00% 99.8 104.3 104.3% 100.00% 99.8 One 102.4 102.4% 99.73%99.8 103.2 103.2% 99.42% 100.0 Three 103.1 103.1% 99.98% 99.8 104.0104.0% 99.96% 99.8 Six 103.3 103.3% 99.98% 99.5 103.5 103.5% 99.95% 99.870 DMSO/ 50 T = 0 52.1 104.2% 99.99% 100.0 52.1 104.2% 99.99% 100.0 30NMP One 51.1 102.1% 99.96% 100.5 50.1 100.3% 99.87% 100.0 Three 51.4102.7% 99.99% 100.0 47.8 95.6% 99.99% 99.8 Six 51.0 102.0% 100.00% 99.549.2 98.3% 99.98% 99.8 100 T = 0 103.6 103.6% 99.99% 100.0 103.6 103.6%99.99% 100.0 One 101.2 101.2% 99.83% 100.5 102.5 102.5% 99.84% 100.7Three 102.3 102.3% 99.99% 99.8 102.3 102.3% 99.97% 99.8 Six 100.8 100.8%100.00% 99.8 98.7 98.7% 99.97% 99.5 Benzyl 50 T = 0 50.4 100.7% 99.86%99.5 50.4 100.7% 99.86% 99.5 Benzoate One 50.3 100.6% 99.99% 100.0 50.2100.4% 99.97% 99.5 Three 50.8 101.6% 99.97% 100.0 50.5 100.9% 99.96%100.0 Six 50.1 100.1% 99.97% 100.0 50.0 100.0% 99.96% 100.0 100 T = 0101.8 101.8% 100.00% 99.3 101.8 101.8% 100.00% 99.3 One 100.0 100.0%99.50% 100.0 100.9 100.9% 99.75% 99.5 Three 100.8 100.8% 99.98% 99.9103.1 103.1% 99.97% 99.8 Six 91.2 91.2% 99.97% 99.1 105.5 105.5% 99.98%99.1

The formulations in Table 4 were placed into syringes (e.g., DaikyoCrystal Zenith syringes). To fill syringes, 500 μL of formulation wasplaced into syringes fitted with needle caps. A long (1½-inch) 20-gaugeneedle) was placed along the inner wall of the syringe barrel and theplunger was guided down into the barrel until the plunger passed the tipof the needle. This allowed air to escape without pushing the sample outof the syringe. Release testing of filled syringes was conducted todetermine drug content (RP-HPLC), purity (RP-HPLC) and transmittance (at630 nm) of the released formulation from the syringe. With the exceptionof two formulations, all release samples had between 100.1% and 105.2%target drug content, with at least 99.97% purity and at least 99.3%transmittance.

Example 2 Pharmacokinetics of Diazepam Formulations

A study was conducted to establish the pharmacokinetic (PK) profile inrats of four concentrated subcutaneous (SC) preparations of diazepamcompared to a control formulation of rectally administered diazepam gel(Diastat, the prevailing at-home treatment for seizures)). Briefly, fivejugular vein-cannulated (JVC) female Sprague-Dawley rats were dosedeither by SC injection with 10 uL of liquid diazepam test article, orrectally with 200 μL of the control preparation utilizing a positivedisplacement pipet. Animals were fasted for 12 hours, and a smallapplication of rectal glycerin prior to Diastat dosing were utilized tominimize defecation and expulsion of drug product in control animals.Whole blood samples were collected at 0 (pre), 3, 6, 9, 12, 20, 30, 45minutes; 1, 1.5, 2, 3, and 4 hours post drug administration in conicaltubes pre-loaded with potassium EDTA anti-coagulant. Plasma diazepam wasanalyzed as described below. Results are presented in FIG. 1. Thepreclinical study was performed at Southwest Bio-Labs (Las Cruces, N.Mex.). The study design is summarized in Table 5.

TABLE 5 Group Rats per Test Article/ Dose Route of Target Dose SampleTime No. Group Formulation Volume (μl) Administration (mg/rat) Points* 15 Diastat Rectal Gel^(a) 200 Rectal 1 0 (pre), 3, (Control) 6, 9, 12, 25 XeriSol ™ Diazepam 10 SC 1 20, 30, 45 DMSO minutes; 1, 3 5 XeriSol ™Diazepam 10 SC 1 1.5, 2, 3, DMSO:NMO 70:30 and 4 h 4 5 XeriSol ™Diazepam 10 SC 1 post-drug NMP admin. 5 5 XeriSol ™ Diazepam 10 SC 1Benzyl Benzoate ^(a)Diastat rectal gel is a non-sterile diazepam gelprovided in a prefilled, unit-dose, rectal delivery system. Diastatrectal gel contains 5 mg/mL diazepam, propylene glycol, ethyl alcohol(10%), hydroxypropyl methylcellulose, sodium benzoate, benzyl alcohol(1.5%), benzoic acid and water, pH between 6.5-7.2.There were a few noteworthy deviations from the study plan. The jugularvein cannulas presented some difficulty to study personnel and did notmaintain patency throughout the study. Some blood collections wereconsequently delayed by a matter of minutes (each actual collection timewas recorded by study personnel). Problems with the JVC caused animalsin each of the XeriSol™ groups to require blood sampling from theretro-orbital sinus at various time points. One animal each in theDiastat and XeriSol™ DMSO groups were removed from the study due tocomplete cannula failure (prior to substituting retro-orbital bleeds).Actual collection times were used to generate individual animaltime-concentration curves from which pharmacological parameters werederived.

Diazepam plasma concentrations were measured at ICON DevelopmentSolutions, LLC (Whitesboro, N.Y.). ICON used an LC/MS/MS methodvalidated for assay of diazepam in rat plasma. Samples were frozen atthe preclinical study site and shipped to ICON on dry ice. Averagediazepam concentrations for all groups at nominal intervalspost-administration are shown in FIG. 1.

Pharmacokinetic parameters were calculated from each individual animaland averaged by treatment group. Standard non-compartmental methods wereutilized to perform calculations for C_(max) (the maximum diazepamconcentration), T_(max) (the time that C_(max) was observed, relative todose administration), and AUC (the area under the diazepam concentrationversus time curve from time 0 to 240 minutes). Additionally, theparameter T_(1/2 max) was calculated (the time at which one-half maximumconcentration was observed). This parameter is useful when C_(max)occurs within a broad peak or when levels around C_(max) are reachedquickly and then sustained, as was observed in some groups. T_(1/2 max)was derived by performing a linear regression on the initial absorptionphase of the curves, and using the equationT_(1/2 max)=[(0.5×C_(max))−(y-intercept)]/slope. Analyses of thepharmacokinetic parameters were performed using SAS statisticalsoftware. Bioequivalence could not be determined due to incompleteclearance of the XeriSol diazepam formulations at the end of the study.Data are shown in Table 6.

TABLE 6 Group C_(max), ng/mL Area under the curve T_(max), minutesT_(1/2 max), minutes Diastat 285.00 (44.10)  10380 (5233) 4.5 (1.7) 1.9(0.4) NMP 378.34 (467.53)  31719 (16921) 8.0 (4.2) 3.6 (1.8) DMSO 89.28(34.55) 13936 (2591) 129.8 (127.6) 5.1 (3.1) DMSO/NMP 92.90 (35.20)14967 (5989) 100.2 (127.6) 3.0 (1.0) Benzyl 22.06 (15.61)  4093 (3332)204.0 (80.5)  N/A Benzoate

These data suggest that among the XeriSol™ groups, the order ofeffectiveness of the formulations is NMP>NMP:DMSO>DMSO>benzyl benzoate.It is clear that of the XeriSol™ formulations, NMP has the mostfavorable PK profile and is most comparable to the Diastat control.While all the XeriSol™ formulations, with the exception of benzylbenzoate, have increased AUC over Diastat, three of the XeriSol™formulations fail to reach one third the C_(max) of Diastat. XeriSol™NMP, on the other hand, exceeds the Diastat C_(max) by 33%. Diastat didhave the shortest T_(max) of all groups, but the XeriSol™ formulationsraised plasma diazepam in comparably short times, again with theexception of benzyl benzoate. Whereas T_(max) is large for all butXeriSol™ NMP, T_(1/2 max) demonstrates that this is an artifact ofsustained concentrations of plasma diazepam near (or slightly above) aconcentration that was achieved early in the time course (T_(1/2 max)was not calculated for benzyl benzoate, as C_(max) was reached in onlyone animal; plasma diazepam continuously increased in the other fouranimals).

The differing C_(max)'s between the XeriSol™ formulations may besolubility-related, as the C_(max) trend follows that of diazepamsolubility in the solvents. The time to appear in the blood may begoverned in part by the time required to dissolve diazepam should aprecipitation event occur upon introduction to the aqueous subcutaneousenvironment—an event more likely with a lower solubility limit in thevehicle. This information could be useful for tailoring the PK profilethrough solvent combinations.

Regarding the sustained elevation of plasma diazepam in XeriSol™ groupsrelative to Diastat controls, differences in blood flow might becausative. From a subcutaneous injection site, diazepam presumably wouldenter the general circulation and have more time to accumulate in theblood vs. draining quite directly from the rectal blood supply to theliver for metabolism, as is likely the case with Diastat. Thisphenomenon of sustained concentrations would thus be more difficult tocontrol. However, a sustained blood diazepam, occurring in all XeriSol™groups throughout the duration of the study, while a measure againstbioequivalence with Diastat, could prove beneficial for not only thetreatment of an active seizure, but also for the prevention of follow-onor cluster seizures. This benefit would be particularly realized in theXeriSol™ NMP formulation, considered in combination with its rapidabsorption profile and high C_(max). Such a PK profile could alsoindicate that XeriSol™ diazepam may be able to attain therapeutic levelsof diazepam using less drug substance per dose than Diastat.

Example 3 Solubility of Lorazepam in Biocompatible Non-Aqueous Solvents

Lorazepam, a small molecule anti-anxiety/anti-convulsant agent(MW=321.16 g/mol) was mixed with 1 gram of the following biocompatible,non-aqueous solvent in approximately 10 milligram increments until it nolonger dissolved: benzyl benzoate, DMSO, NMP, Triacetin, and PEG 300.Once 50 mg of drug had been added to the solution (and the drug wasstill completely soluble in the solvent), the increments of drug addedin each step increased to approximately 25 mg, and was maintained atapproximately 25 mg until the drug no longer dissolved completely in thesolution. This allowed the maximum solubility of lorazepam at thisresolution to be determined for each of the five biocompatiblenon-aqueous solvents, as shown in Table 7.

TABLE 7 Solvent Solubility (mg/mL) Solubility Benzyl Benzoate 10Sparingly Soluble DMSO 100 Freely Soluble NMP 480 Freely SolubleTriacetin 20 Sparingly Soluble PEG 300 80 Soluble

Example 4 Solubility of Albuterol Sulfate in Biocompatible Non-AqueousSolvents

Albuterol sulfate, a small molecule immuno-suppressive/anti-cancer agent(MW=288.35 g/mol) Was mixed with the following biocompatible non-aqueoussolvents (benzyl benzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin,and PEG 300) in amounts sufficient to prepare mixtures of increasingconcentration. Specifically, the concentrations examined were 0.1 mg/mL,1.0 mg/mL, 5 mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, andincreasing increments of 50 mg/mL until the small molecule drug nolonger dissolved completely in the solvent. Accordingly, this allowedthe maximum solubility of albuterol sulfate at this resolution to bedetermined for each of the six biocompatible non-aqueous solvents, asshown in Table 8.

TABLE 8 Solubility Solvent (mg/mL) Solubility Benzyl Benzoate <0.1Practically insoluble DMSO 5 Slightly soluble NMP <0.1 Practicallyinsoluble 70:30 DMSO:NMP 5 Slightly soluble Triacetin <0.1 Practicallyinsoluble PEG 300 <0.1 Practically insoluble

Example 5 Solubility of Atropine in Biocompatible Non-Aqueous Solvents

Atropine, a small molecule anti-cholinergic agent (MW=289.4 g/mol) wasmixed with the following biocompatible non-aqueous solvents (benzylbenzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) inamounts sufficient to prepare mixtures of increasing concentration.Specifically, the concentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, and increasingincrements of 50 mg/mL until the small molecule drug no longer dissolvedcompletely in the solvent. Accordingly, this allowed the maximumsolubility of atropine at this resolution to be determined for each ofthe six biocompatible non-aqueous solvents, as shown in Table 9.

TABLE 9 Solvent Solubility (mg/mL) Solubility Benzyl Benzoate 30 SolubleDMSO 500 Freely soluble NMP 750 Freely soluble 70:30 DMSO:NMP 650 Freelysoluble Triacetin 5 Slightly soluble PEG 300 30 Soluble

Example 6 Solubility of Cromolyn Sodium in Biocompatible Non-AqueousSolvents

Cromolyn sodium, a small molecule mast cell stabilizer (MW=512.3 g/mol)was mixed with the following biocompatible non-aqueous solvents (benzylbenzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) inamounts sufficient to prepare mixtures of increasing concentration.Specifically, the concentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, and increasingincrements of 50 mg/mL until the small molecule drug no longer dissolvedcompletely in the solvent. Accordingly, this allowed the maximumsolubility of cromolyn sodium at this resolution to be determined foreach of the six biocompatible non-aqueous solvents, as shown in Table10.

TABLE 10 Solubility Solvent (mg/mL) Solubility Benzyl Benzoate 0.1 Veryslightly soluble DMSO 50 Soluble NMP 0.1 Very slightly soluble 70:30DMSO:NMP 5 Slightly soluble Triacetin 0.1 Very slightly soluble PEG 30050 Soluble

Example 7 Solubility of Lidocaine in Biocompatible Non-Aqueous Solvents

Lidocaine, a small molecule (MW=234.34 g/mol) was mixed with thefollowing biocompatible non-aqueous solvents (benzyl benzoate, DMSO,NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) in amounts sufficientto prepare mixtures of increasing concentration. Specifically, theconcentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5 mg/mL, 10 mg/mL, 30mg/mL, 50 mg/mL, 100 mg/mL, and increasing increments of 50 mg/mL untilthe small molecule drug no longer dissolved completely in the solvent.Accordingly, this allowed the maximum solubility of lidocaine at thisresolution to be determined for each of the six biocompatiblenon-aqueous solvents, as shown in Table 11.

TABLE 11 Solvent Solubility (mg/mL) Solubility Benzyl Benzoate 900Freely Soluble DMSO 2000 Very soluble NMP 1750 Very soluble 70:30DMSO:NMP 1750 Very soluble Triacetin 400 Freely soluble PEG 300 200Freely soluble

Example 8 Solubility of Rifampicin in Biocompatible Non-Aqueous Solvents

Rifampicin, a small molecule anti-tubercular agent (MW=822.94 g/mol) wasmixed with the following biocompatible non-aqueous solvents (benzylbenzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) inamounts sufficient to prepare mixtures of increasing concentration.Specifically, the concentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, and increasingincrements of 50 mg/mL until the small molecule drug no longer dissolvedcompletely in the solvent. Accordingly, this allowed the maximumsolubility of rifampicin at this resolution to be determined for each ofthe six biocompatible non-aqueous solvents, as shown in Table 12.

TABLE 12 Solvent Solubility (mg/mL) Soluble Benzyl Benzoate 50 SolubleDMSO 150 Freely soluble NMP 400 Freely soluble 70:30 DMSO:NMP 150 Freelysoluble Triacetin 5 Slightly soluble PEG 300 5 Slightly soluble

Example 9 Solubility of Epinephrine Bitartrate in BiocompatibleNon-Aqueous Solvents

Epinephrine bitartrate, a small molecule sympathomimetic (MW=333.3g/mol) was mixed with the following biocompatible non-aqueous solvents(benzyl benzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG300) in amounts sufficient to prepare mixtures of increasingconcentration. Specifically, the concentrations examined were 0.1 mg/mL,1.0 mg/mL, 5 mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, andincreasing increments of 50 mg/mL until the small molecule drug nolonger dissolved completely in the solvent. Accordingly, this allowedthe maximum solubility of epinephrine bitartrate at this resolution tobe determined for each of the six biocompatible non-aqueous solvents, asshown in Table 13.

TABLE 13 Solvent Solubility (mg/mL) Solubility Benzyl Benzoate <0.1Practically insoluble DMSO 700 Freely soluble NMP 400 Freely soluble70:30 DMSO:NMP 500 Freely soluble Triacetin <0.1 Practically insolublePEG 300 0.1 Very slightly soluble

Example 10 Solubility of Acetylsalicylic Acid in BiocompatibleNon-Aqueous Solvents

Acetylsalicylic acid, a small molecule analgesic agent (MW=180.16 g/mol)was mixed with the following biocompatible non-aqueous solvents (benzylbenzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) inamounts sufficient to prepare mixtures of increasing concentration.Specifically, the concentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, and increasingincrements of 50 mg/mL until the small molecule drug no longer dissolvedcompletely in the solvent. Accordingly, this allowed the maximumsolubility of acetylsalicylic acid at this resolution to be determinedfor each of the six biocompatible non-aqueous solvents, as shown inTable 14.

TABLE 14 Solvent Solubility (mg/mL) Solubility Benzyl Benzoate 30Soluble DMSO 2000 Very soluble NMP 1200 Very soluble 70:30 DMSO:NMP 1450Very soluble Triacetin 5 Slightly soluble PEG 300 5 Slightly soluble

Example 11 Solubility of Beclomethasone Dipropionate in BiocompatibleNon-Aqueous Solvents

Beclomethasone dipropionate, a small molecule corticosteroid (MW=521.04g/mol) was mixed with the following biocompatible non-aqueous solvents(benzyl benzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG300) in amounts sufficient to prepare mixtures of increasingconcentration. Specifically, the concentrations examined were 0.1 mg/mL,1.0 mg/mL, 5 mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, andincreasing increments of 50 mg/mL until the small molecule drug nolonger dissolved completely in the solvent. Accordingly, this allowedthe maximum solubility of beclomethasone dipropionate at this resolutionto be determined for each of the six biocompatible non-aqueous solvents,as shown in Table 15.

TABLE 15 Solvent Solubility (mg/mL) Soluble Benzyl Benzoate 50 SolubleDMSO 1700 Very soluble NMP 1800 Very soluble 70:30 DMSO:NMP 1700 Verysoluble Triacetin 5 Slightly soluble PEG 300 30 Soluble

Example 12 Solubility of Sumatriptan Succinate in BiocompatibleNon-Aqueous Solvents

Sumatriptan succinate, a small molecule anti-migraine drug (MW=413.49g/mol) was mixed with the following biocompatible non-aqueous solvents(benzyl benzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG300) in amounts sufficient to prepare mixtures of increasingconcentration. Specifically, the concentrations examined were 0.1 mg/mL,1.0 mg/mL, 5 mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, andincreasing increments of 50 mg/mL until the small molecule drug nolonger dissolved completely in the solvent. Accordingly, this allowedthe maximum solubility of sumatriptan succinate at this resolution to bedetermined for each of the six biocompatible non-aqueous solvents, asshown in Table 16.

TABLE 16 Solvent Solubility (mg/mL) Soluble Benzyl Benzoate <0.1Practically insoluble DMSO 350 Freely soluble NMP 100 Freely soluble70:30 DMSO:NMP 300 Freely soluble Triacetin <0.1 Practically insolublePEG 300 0.1 Very slightly soluble

Example 13 Solubility of Diphenhydramine Hydrochloride in BiocompatibleNon-Aqueous Solvents

Diphenhydramine hydrochloride, a small molecule anti-histamine drug(MW=291.82 g/mol) was mixed with the following biocompatible non-aqueoussolvents (benzyl benzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin,and PEG 300) in amounts sufficient to prepare mixtures of increasingconcentration. Specifically, the concentrations examined were 0.1 mg/mL,1.0 mg/mL, 5 mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, andincreasing increments of 50 mg/mL until the small molecule drug nolonger dissolved completely in the solvent. Accordingly, this allowedthe maximum solubility of diphenhydramine hydrochloride at thisresolution to be determined for each of the six biocompatiblenon-aqueous solvents, as shown in Table 17.

TABLE 17 Solvent Solubility (mg/mL) Soluble Benzyl Benzoate 0.1 Veryslightly soluble DMSO 300 Freely soluble NMP 100 Freely soluble 70:30DMSO:NMP 150 Freely soluble Triacetin 0.1 Very slightly soluble PEG 30050 Soluble

Example 14 Solubility of Fluconazole in Biocompatible Non-AqueousSolvents

Fluconazole, a small molecule anti-fungal drug (MW=306.27 g/mol) wasmixed with the following biocompatible non-aqueous solvents (benzylbenzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) inamounts sufficient to prepare mixtures of increasing concentration.Specifically, the concentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, and increasingincrements of 50 mg/mL until the small molecule drug no longer dissolvedcompletely in the solvent. Accordingly, this allowed the maximumsolubility of fluconazole at this resolution to be determined for eachof the six biocompatible non-aqueous solvents, as shown in Table 18.

TABLE 18 Solvent Solubility (mg/mL) Solubility Benzyl Benzoate 5Slightly soluble DMSO 900 Freely soluble NMP 800 Freely soluble 70:30DMSO:NMP 850 Freely soluble Triacetin 5 Slightly soluble PEG 300 50Soluble

Example 15 Solubility of Tobramycin in Biocompatible Non-AqueousSolvents

Tobramycin, a small molecule aminoglycoside antibiotic (MW=467.51 g/mol)was mixed with the following biocompatible non-aqueous solvents (benzylbenzoate, DMSO, NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) inamounts sufficient to prepare mixtures of increasing concentration.Specifically, the concentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5mg/mL, 10 mg/mL, 30 mg/mL, 50 mg/mL, 100 mg/mL, and increasingincrements of 50 mg/mL until the small molecule drug no longer dissolvedcompletely in the solvent completely in the solvent. Accordingly, thisallowed the maximum solubility of tobramycin at this resolution to bedetermined for each of the six biocompatible non-aqueous solvents, asshown in Table 19.

TABLE 19 Solvent Solubility (mg/mL) Solubility Benzyl Benzoate <0.1Practically insoluble DMSO <0.1 Practically insoluble NMP <0.1Practically insoluble 70:30 DMSO:NMP <0.1 Practically insolubleTriacetin 0.1 Very slightly soluble PEG 300 0.1 Very slightly soluble

Example 16 Solubility of Cyclophosphamide Monohydrate in BiocompatibleNon-Aqueous Solvents

Cyclophosphamide monohydrate, a small moleculeimmuno-suppresive/anti-cancer agent (MW=279.10 g/mol) was mixed with thefollowing biocompatible non-aqueous solvents (benzyl benzoate, DMSO,NMP, 70:30 (v/v) DMSO:NMP, Triacetin, and PEG 300) in amounts sufficientto prepare mixtures of increasing concentration. Specifically, theconcentrations examined were 0.1 mg/mL, 1.0 mg/mL, 5 mg/mL, 10 mg/mL, 30mg/mL, 50 mg/mL, 100 mg/mL, and increasing increments of 50 mg/mL untilthe small molecule drug no longer dissolved completely in the solvent.Accordingly, this allowed the maximum solubility of cyclophosphamidemonohydrate at this resolution to be determined for each of the sixbiocompatible non-aqueous solvents, as shown in Table 20.

TABLE 20 Solvent Solubility (mg/mL) Soluble Benzyl Benzoate 100 Freelysoluble DMSO 2800 Very soluble NMP 2100 Very soluble 70:30 DMSO:NMP 2700Very soluble Triacetin 150 Freely soluble PEG 300 100 Freely soluble

* * *

All of the ingredients, compositions, or methods disclosed and claimedin this specification can be made and executed without undueexperimentation in light of the present disclosure. While theingredients, compositions, or methods of this invention have beendescribed in terms of particular embodiments, it will be apparent tothose of skill in the art that variations may be applied to the activeingredients, compositions, or methods and in the steps or in thesequence of steps of the method described herein without departing fromthe concept, spirit and scope of the invention.

The invention claimed is:
 1. A method for treating or preventinganxiety, muscle spasms, or seizures, the method comprising parenterallyadministering to a subject in need thereof a stable liquid formulationcomprising: (a) a biocompatible solvent consisting of dimethylsulfoxide(DMSO) or a mixture of DMSO and n-methyl pyrrolidone (NMP); and (b) asmall molecule drug, or a salt thereof, solubilized within the solvent,wherein the small molecule drug is diazepam, and wherein diazepam ispresent in the liquid formulation in an amount up to its solubilitylimit in the formulation, wherein the liquid formulation comprises lessthan 5% by weight residual water, and wherein a volume of the liquidformulation to be parenterally injected is 3 ml or less.
 2. The methodof claim 1, further comprising the injectable volume within a device fordispensing the liquid formulation.
 3. The method of claim 2, wherein thedevice is a syringe, a pen injection device, an auto-injector device, anexternal or implantable pump, or a perfusion bag.
 4. The method of claim1, wherein the liquid formulation comprises 50 mg/ml to 300 mg/ml ofdiazepam.
 5. The method of claim 1, wherein the volume of the liquidformulation to be parenterally injected is from 0.1 μl to 1 μl.
 6. Themethod of claim 1, wherein the volume of the liquid formulation to beparenterally injected is from 1 μl to 10 μl.
 7. The method of claim 1,wherein the volume of the liquid formulation to be parenterally injectedis from 10 μl to 1 ml.
 8. The method of claim 1, wherein the liquidformulation is not diluted prior to administration.